Research in the Garner lab focuses on the development of new enabling chemistries and the synthesis of biologically active molecules. In this context, our intellectual activities may be viewed as architecture (design and construction) on the molecular scale. Chemical synthesis (the discipline associated with building molecular structures) is the common element that underlies all of our research endeavors.
Current research projects include the development of new methodology for the convergent synthesis and site-specific modification of proteins as well as the application of the asymmetric [C+NC+CC] coupling reaction to synthesize biologically active pyrrolidine-containing targets.
Research highlights from the Garner Lab
Garner, P.; Cox, P. B.; Rathnayake, U.; Holloran, N.; Erdman, P. ACS Med. Chem. Lett. 2019, 105, 811.
Fragment-based drug discovery (FBDD) is a well-established technology for lead compound generation in drug discovery. As this technology has evolved, the design of fragments for screening has also evolved to engender not just an understanding of the role of modulating the physicochemical properties of fragments (Rule of Three, Ro3) but also the importance and implications of incorporating shape and, in particular, 3D characteristics into fragments. Herein, we describe the design and synthesis of pyrrolidine-based fragments with good fragment-like (Ro3) physicochemical properties that effectively sample three-dimensional molecular space.
Xuan, W.; Collins, D.; Koh, M.; Yao, A.; Xiao, H.; Garner, P.; Schultz, P. G. ACS Chem. Biol. 2018, 13, 578.
Here, we report the site-specific incorporation of a thioester containing noncanonical amino acid (ncAA) into recombinantly expressed proteins. Specifically, we genetically encoded a thioester-activated aspartic acid (ThioD) in bacteria in good yield and with high fidelity using an orthogonal nonsense suppressor tRNA/aminoacyl-tRNA synthetase (aaRS) pair. To demonstrate the utility of ThioD, we used native chemical ligation to label green fluorescent protein with a fluorophore in good yield.
Joseph, R.; Morales-Padilla, M.; Garner, P. Tetrahedron Lett. 2015, 56, 4302.
The Fmoc-based solid phase synthesis of unprotected ω-aspartic thioacid containing peptides is demonstrated. The method involves the novel use of a silyl ester as a carboxylate surrogate for mild peptide bond formation in the presence of a reactive ω-aspartyl thioester. The resulting peptide thioacids may be used in N-glycoligation and other thioacid-mediated conjugation reactions.
Murray, C.; Dryer, F. B.; Garner, P. Tetrahedron Lett. 2015, 56, 3636.
A general synthesis of N-terminal aziridinyl-2-carbonyl (Azy) peptides has been developed aided by the photolabile o-nitrophenylethyl protecting group. This method enables the synthesis of unprotected Azy-terminated peptides incorporating ionizable groups using solid phase techniques followed by photorelease of the free N-terminal Azy moiety. The resulting Azy peptides undergo Cu(II)-mediated ligation with thioacids to give Azy-embedded peptides, providing a handle for site-specific modification of the peptide.
Weerasinghe, L.; Van Houten, I.; Hu, J.; Garner, P. Chem. Comm. 2014, 50, 4908.
A 15-step synthesis of the iGluR antagonist kaitocephalin from aspartic acid is reported. The linchpin pyrrolidine ring of the target molecule is efficiently assembled with in a single operationvia an asymmetric [C+NC+CC] reaction.
Joseph, R.; Murray, C.; Garner, P. Org. Lett. 2014, 16, 1550.
A catalytic asymmetric version of the exo-selective [C+NC+CC] reaction is reported. This multicomponent reaction utilizes a readily prepared achiral glycyl sultam as the “NC” component and commercially available catalyst components. The method can be applied to a variety of aldehydes (“C” component) and activated alkenes (“CC” component) to provide substituted pyrrolidines in good yields and high enantioselectivities. Of particular note is the ability to employ labile enolizable aldehydes (e.g., acetaldehyde and propionaldehyde) in this reaction.